Analysis of molecular mechanisms of development of mammalian eyes, brain, kidney and heart regulated by tyrosine kinases

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 18590258
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: GOTOH Noriko The University of Tokyo, Institute of Medical Science, Associate Professor (10251448)
• Project Period (FY): 2006 – 2007
• Keywords: stem cells / neuron / neural crest / FGF / adaptor molecule

Research Abstract

1. Analysis of molecular mechanisms of development through FRS2alpha-Shp2 pathway. We show that the carotid body is absent in FRS2alpha2F/2F mice and that the carotid body rudiment is not formed in the wall of the third arch artery in mutant embryos. We propose that the sympathetic ganglion provides glomus cell precursors into the third arch artery derivative.
2. An FGF4-induced Cdx2-mediated BMP4 signaling pathway regulates a stem cell niche in mammalian embryos. We provide evidence that FGF4 derived from the ICM activates an FRS2alpha-ERK pathway resulting in enhanced expression of transcription factor Cdx2 in trophoblast stem cells. Cdx2 In turn binds to an FGF4-responsive enhancer element of the promoter region of Bmp4, leading to production and secretion of Bmp4.
3. FRS2alpha mediates FGF signaling for the proliferation and self-renewal of neural stem/progenitor cells (NSPCs). Expression of wild type FRS2alpha promoted the proliferation of NSPCs in the presence of FGF2 but not EGF. The knockdown of FRS2alpha resulted in a reduction in proliferation of NSPCs. We demonstrate that FGF2-induced tyrosine phosphorylation of FRS2alpha is important not only for the proliferation but also for the self-renewal of NSPCs and raise a possibility of manipulating FRS2alpha in NSPCs for cell replacement therapy.

Research Products

• [Journal Article] Feedback inhibitors of the epidermal growth factor receptor signaling pathways. (2008)
  • Author(s): Gotoh, N
  • Journal Title: The International Journal of Biochemistry & Cell Biology (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. (2008)
  • Author(s): Gotoh, N
  • Journal Title: Cancer Sci. (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] FRS2alpha2F/2F mutant mice lack the carotid body and exhibit sympathetic ganglia and carotid sinus nerve abnormalities. (2008)
  • Author(s): Kameda, Y., Ito, M., Nishimaki, T. and Gotoh, N.
  • Journal Title: Dev. Biol. 314 Pages: 236-247
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins (2008)
  • Author(s): Gotoh, N.
  • Journal Title: Cancer Sci., published on line
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] FRS2α^<2F/2F> mutant mice lack the carotid body and exhibit sympathetic ganglia and carotid sinus nerve abnormalities (2008)
  • Author(s): Kameda, Y., Ito, M., Nishimaki T. and Gotoh, N.
  • Journal Title: Dev. Biol 314 Pages: 236-247
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EGFR phosphorylation-dependent formation of cell-cell contacts by Ras/Erks cascade inhibition. (2007)
  • Author(s): Kang, E.S., Oh, M.A., Lee, S.A., Kim, T.Y., Kim, S.H., Gotoh, N., Kim, Y.N. and Lee, J.W.
  • Journal Title: Biochem. Biophys. Acta. 1773 Pages: 833-843
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] EGFR phosphorylation-dependent formation of cell-cell contacts by Ras/Erks cascade inhibition (2007)
  • Author(s): Kang, E. S., Oh, M. A., Lee, S. A., Kim, T. Y., Kim, S. H., Gotoh, N., Kim, Y. N. and Lee, J. W.
  • Journal Title: Biochim. Biophys. Acta 1773 Pages: 833-843
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Unique role of SNT-2/FRS2beta/FRS3 docking/adaptor protein for Negative regulation in EGF receptor tyrosine kinase signaling pathways (2006)
  • Author(s): Huang, et. al.
  • Journal Title: Oncogene 25 Pages: 6457-6466
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Unique role of SNT-2/FRS2β/FRS3 ducking/adaptor protein for negative regulation of EGF receptor tyrosine kinase pathways (2006)
  • Author(s): Huang, L., Watanabe, M., Chikamori, M., Kido, Y., Yamamoto, T., Shibuya, M., Gotoh, N. and Tsuchida. N.
  • Journal Title: Oncogene 25 Pages: 6457-6466
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Feedback inhibitors of epidermal growth factor receptor signaling pathways
  • Author(s): Gotoh, N.
  • Journal Title: Int. J. Biocheuz. Cell Biol
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Membrane-linked docking protein
  • Author(s): Gotoh, N. and Tsuchida, N.
  • Journal Title: Encyclopedia of Cancer 2nd Edition, Springer, Heidelberg, Germany (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Funcional analysis of FRS2alpha in neuroal stem/progenitor cells (2007)
  • Author(s): Takuya Sato
  • Organizer: Annual Meeting of Biochemistry and Molecular Biology, Japan
  • Place of Presentation: Yokuhama
  • Year and Date: 20070000
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 神経幹細胞および前駆細胞におけるFRS2alphaの機能解析 (2007)
  • Author(s): 佐藤琢也
  • Organizer: 分子生物学会2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Encyclopedia of Cancer, 2nd Edition (2008)
  • Author(s): Gotoh, N. and Tsuchida, N.
  • Publisher: Springer, Heidelberg, Germany
  • Description: 「研究成果報告書概要(和文)」より